Literature Review Area
Holding space for lit. reviews for the project. Conformations of immunoglobulin hypervariable regions (1989) * Gen: Most sequence changes at a given CDR alter the binding surface slightly while maintaining the canonical form. Some induce conformational change – change in canonical form. * This model explains most of the variation in L1-3, H1-2. * HV regions – tend to be of approximately the same size, with same/closely related residues. * Model validation and testing dependent on: ** correct determination of take-off point ** correct determination of the relative importance of conserved residues ** up/down-stream residue change not significantly affecting canonical structure conformations * Paper test 4 IGs using this model, prior to their crystallographic elucidation (HyHEL 5,10, NC41, NQ10) * AA sequence analysis – 19/24 HV regions with conformations approximate to known canonical forms * Each HV region examined to determine; ** size – comparison to known homologous Hvs ** sequence – similar to residues producing a known conformations * NB: inclusion of pre-takeoff range will skew results, antigen-antibody conformational change an issue * Glycine position a key determinant of loop form – small turn conformation. * Fairly high risk of over-fitting if using the corrective model described here – assesses test subject against training set, then alters algorithm (adding new rules) and repeats * Basic point: fairly good evidence for canonical form model in L1-3, H1+2. Should take best advantage of new availability of structural data. Standard conformations for the canonical structures of immunoglobulins (1997) * Very similar local conformations are possible even when the position relative to the framework differs substantially. * 85% of 244HVs(from 49 IG Fab) classified as a member of a known canonical form: a useful but incomplete description of the chemical space * L1 (V-Kappa); ** packs across top of the V-kappa domain, briding 2 beta-sheets ** Kabat (1979): *** Residues 24-34 first CDR *** Varies – addition or deletion at residue 27 site *** NB: Doesn't mean that the indel site describes the whole CDR ** Chothia and Lesk (1987): *** Residues 26-32 *** Indels at residue 30 ** Six identified canonical forms (as of 1997), with their numbering primarily reflecting the order of their discovery. ** NB: torsion angle used as a descriptor/comparator – likely to be useful. ** Residues between 30+32 vary from 0-7 in the 6 identified forms ** Inital studies suggested that for all 6 structures, res 26-9 and 32 have a common conformation that packs against the framework ** The second canonical structure has two alternative forms (A+B – might be better to call these isoforms really?) ** These might not be meaningful – could have captured two points on a continuum of change, for example. * L1 (V-Lambda); ** Kabat (1979): *** Residues 24-34 identified on the basis of sequence variation ** Chothia and Lesk (1987): *** Residues 26-32: 25 not part of the framework region in certain v-lambda structures ** 4 canonical structures identified, with 25-32 indel region being 9-11 residues long, with a near-centre hydrophobic cavity residue – numbered as 30 in this work, used as the basis for the rest of the structural numbering *** NB: this sort of signposting could be very useful if reasonably easy to identify ** Again – most residue changes/ small indels do not alter the canonical conformation adopted. ** Two alternate forms to canonical form 3 in this case. * L2 ** In hairpin linking C' and C'' strands'' ** Kabat (1979): *** Res 50-56 ** Chothia and Lesk (1987) *** 50-52 in both lambda and kappa domains *** Only one canonical structure. - RMSD: 0.1-0.5 Angstrom *** Classic gamma-turn – strained conformation. ** This residues form a three-res hairpin loop linking 49 -> 53, which are themselves linked by H-bonds. * L3 (V-Kappa): ** Kabat (1979): *** Res 89-96 ** Chothia and Lesk (1987): *** 91-96 in both lambda and kappa domains ** 6 canonical structures described ** NB: unbound/bound form – 120 degree rotation on 92-93 bond in conventional form (canonical form 1) * L3 (V-Lambda): ** 2 canonical forms – 6 residue loop with two top residues forming the turn/eight residue loop with 4 determining the turn * H1 ** packs accross the top of the VH domain – bridging the beta-sheets. ** Kabat (1979): *** 31-35 *** insertions at a site following 35 ** Chothia and Lesk (1987): *** 26-32 *** Indels at site 31 *** 3 canonical structures – 1 most common ** Wide range in size of hydrophobic residue sites 24, 29, 34. * H2 ** Kabat (1979): *** Res 50-65 ** Chothia (1987): *** 56-58 form short C'' strand, conformational region is AA 52-56'' *** 4 canonical structures ** 1: shortest loop ** 2: 4-residue loop with A/B conformation – 160 degree rotation at 52a/53 in B ** 3: 4-residue loop, considerably different conformation to 2 though – A/B/C conformational possibilities. B/C - 3 out of 4 residues GLY – relatively high degree of conformational freedom – non-standard varations from canonical form. ** 4: 6-residue loop: much as 2, similar extent of rotational variability. * H3 ** Kabat (1979): *** Res 95-102 *** Insertions at res 100 – a/b/c/etc. ** Not particularly well understood at this point. ** In loops with 11+ residues between Cys-92 and Gly-104 it is v. common for 92-96 and 101(-2)-101-104 to form an anti-parallel two-strand beta-sheet. ** Again – torsional angle comparison and rigid-body superposition performed. ** NB: Even in cases with non-adoption of this structural motif in the native form, it is commonly adopted in the bound-state of that antibody – induced by antibody-antigen interactions * Clustering; ** Refers to another paper – Martin and Thornton (1996) ** Difficult to distinguish between alpha-carbon and carbonyl oxygen at the 3-angstrom range – paper suggests that structures solved at 2.7A or better that do not match known canonical forms should be considered as possible alternatives. * Basic point: considerable variation between systems in the residues they identify as important. Need to consider torsional effects as well as backbone RMSD. Canonical forms are themselves subdivided – although whether these are truly different or represent a range of allowed conformations is unclear to me.